Bone Hormone Linked to Obesity and Type 2 Diabetes

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Even though bones seem to be metabolically inactive structures, nothing could be further from the truth. In fact, bones are rebuilt constantly through the action of cells known as osteoblasts while old bone is destroyed by other cells known as osteoclasts. Bones also produce red and white blood cells, help maintain blood pH and store calcium. However, exciting new research has shown that bones also act as an endocrine organ. Not only do bones produce a protein hormone, osteocalcin (pictured), that regulates bone formation, but this hormone also protects against obesity and glucose intolerance by increasing proliferation of pancreatic beta cells and their subsequent secretion of insulin. Osteocalcin was also found to increase the body's sensitivity to insulin and as well as reducing its fat stores.

Hormones function as chemical messengers that allow the body to precisely coordinate metabolism, reproduction and other essential biological processes that involve multiple organs.

"The skeleton used to be thought of as just a structural support system. This opens the door to a new way of seeing the bones," said Dr. Gerard Karsenty, chairman of the department of genetics and development at Columbia University Medical Center in NYC, who headed the team that made the discovery.

Osteocalcin is not new to science: Its existence has been known for 50 years, "but its function was never understood," observed Karsenty. However, researchers have long known that people with diabetes tend to have low levels of osteocalcin, but until now no one understood the significance.

Based on their knowledge of skeletal biology and endocrinology, the research team hypothesized that there might be a relationship between skeletal biology and endocrine regulation because of the long-known observation that obesity protects against osteoporosis in mammals. Additionally, it was known that people with untreated type 2 diabetes have low osteocalcin levels, which made this hormone an appealing target for their research efforts.

To do this research, the scientists designed an elegant series of experiments using several groups of mice. The first group of experimental mice had their osteoblast gene, called Esp, genetically deactivated, or "knocked out". Esp encodes a receptor-like protein tyrosine phosphatase called OST-PTP that increases beta-cell proliferation and insulin secretion in the pancreas, which results in hypoglycemia. But these so called "knock-out mice" lacked all functional Esp genes, so their insulin secretion and sensitivity decreased causing them to become obese and then to develop Type 2 diabetes when fed a normal diet. Type 2 diabetes occurs when the body becomes resistant to insulin, the hormone that regulates sugar metabolism.

A second group of experimental mice were genetically engineered to over-produce osteocalcin. These mice showed lower-than-normal blood glucose levels and higher insulin levels than did normal mice that were fed a normal diet. Additionally, these "overproducer mice" also showed increased insulin sensitivity. This is probably the most exciting result because typically, excess blood insulin decreases tissues' sensitivity to the hormone, which makes insulin treatment difficult for diabetics. Further, the team found that treating the "knock-out mice" with osteocalcin helped regulate their blood sugar and insulin.

Additionally, the investigators reported that mice with one functional copy of Esp showed a significant reversal of their metabolic abnormalities, which provides "genetic evidence that Esp and osteocalcin lie in the same regulatory pathway and that [the] Esp-/- mice metabolic phenotype is caused by a gain-of-activity of this hormone."

Interestingly, mice that are genetically programmed to overeat and mice that were fed fatty diets were prevented from suffering both obesity and diabetes when given high levels of osteocalcin. Karsenty is now determining whether giving osteocalcin to his diabetic "knock-out mice" will reverse the disease. This research shows promise for treating human diabetics as well.

Finding a substance that increases beta cell proliferation, says Karsenty, "is a holy grail for diabetes research." Thus, if what's true for mice also proves true for humans, "then we have inside us a hormone that does precisely this."

"The findings could have important implications for the treatment of diabetes. Osteocalcin has a triple-punch effect, in that it raises both insulin levels and insulin uptake while keeping fat at bay. That makes it a promising therapy for middle-aged people who want to fight type 2 diabetes," Karsenty said.

Additionally, this study also reveals that the skeleton is an important part of the endocrine system.

"To our knowledge this study provides the first in vivo evidence that [the] skeleton exerts an endocrine regulation of energy metabolism and thereby may contribute to the onset and severity of metabolic disorders," the authors wrote in their paper.

This research was published in the August 10 issue of Cell.


"Endocrine regulation of energy metabolism by the skeleton" by Na Kyung Lee, Hideaki Sowa, Eiichi Hinoi, Mathieu Ferron, Jong Deok Ahn, Cyrille Confavreux, Romain Dacquin, Patrick J. Mee, Marc D. McKee, Dae Young Jung, Zhiyou Zhang, Jason K. Kim, Franck Mauvais-Jarvis, Patricia Ducy, and Gerard Karsenty. Cell 2007;130: 456-469. [abstract or free PDF]

Osteocalcin cartoon source.

LATimes (quotes)

Time (quotes)

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Some scientists claim that fluoridated water impairs bone growth and function. Could one hypothesize that fluoridated water is responsible for the epidemic of diabetes in the United States?

I suppose one reason the skeleton's endocrine role was not noticed before is that the function is not localized. It leads me to wonder what other biological functions are so distributed (perhaps, instead, in muscle or brain tissue, or in artery walls), and why some endocrine activities are and others aren't.

Certainly, it's easier to imagine specialized endocrine cells arising from a single blastoma cell, and thus developing into a recognizable organ. At the same time, most cells near capillaries don't seem to benefit much from that kind of specialization. Any cell could produce hormones in practical amounts without compromising its other activities.

I'm guessing that the distributed endocrine systems will turn out to produce hormones traceable in some form to our least-specialized ancestors, e.g sponges.

Or, is there some functional benefit to endocrine cells clustering in one place, and/or specializing?

By Nathan Myers (not verified) on 13 Aug 2007 #permalink

I think we will find, eventually, that our conception of the body is misleading and terribly oversimplified. We tend to think of an organism as being made up of "systems." However, the body does not know it has systems like that, and there is no particular reason for it to limit itself to our peculiar way of conceptualizing things.

It might not be too far off, to think that every part of the body is constantly in communication with every other part.

Pretty amazing, right? They've found that everything inside our skin is connected to everything else, and that bones aren't just hangers for muscles and organs. So bones are the newest "endocrine" organ. That's just another reason not to ignore them.

Some people claim that the frequent use of high fructose corn syrup is responsible for the diabetes epidemic in the US:

Still others blame eating too many carbohydrates to follow a low-fat diet:

Other people blame Agent Orange:

Still others blame drinking water containing too much arsenic:;_y…

In other words, it's blamed on too many causes to assume that any of that are right without more research.

By robertmiles (not verified) on 24 Aug 2008 #permalink